1. Field of the Invention
7α-methoxy-cephalosporins are a particular class of cephalosporins having a methoxy group in position 7α. This methyl group confers marked stability against the action of various β-lactams, for which reason certain representatives of this cephalosporin class have entered into clinical use. The most well known are cefoxitin, cefmetazol and cefotetan, however 6α-methoxy-penicillin and 7α-methoxy-oxacephalosporin homologues also exist.
2. Discussion of the Background
The process used for introducing the methoxy group into position 7α of cephalosporins and 6α of penicillins is hence of evident importance. U.S. Pat. No. 4,109,084, U.S. Pat. No. 4,158,657, U.S. Pat. No. 4,154,927 and U.S. Pat. No. 4,119,778 claim methods for preparing cephalosporin thiooximes characterised by the R1—S—N=group in position 7. In particular, U.S. Pat. No. 4,119,778, U.S. Pat. No. 4,154,927 and U.S. Pat. No. 4,158,657 claim penicillin and cephalosporin thiooximes in which a (1-methyl-1H-tetrazol-5-yl) thiomethyl is also present in position 3, and a method for their preparation starting from 6-APA, 7-ADCA, 7-ACA and derivatives; in the case in point, the said tetrazole group is a substituent of the cefmetazol molecule, one of the 7α-methoxy-cephalosporins which have long entered into clinical use.
The 7α-methoxy nuclei can be obtained from these thiooximes by treatment with triphenylphosphine and a suitable catalyst in the presence of methanol. The 7α-methoxy nuclei obtained in this manner are then transformed into the corresponding acylamino derivatives, i.e. into the 7β-acylamino-7α-cephalosporins or into the relative intermediates for their preparation.
Unfortunately, the aforesaid process has the drawback of providing a product which is impure because of the presence of 7α-methylthio derivatives, as described in J.A.C.S. 1980, 120, pp 1690-1702, originating from a transposition of the —SH3 group of an intermediate adduct linked to triphenylphosphine. The impurity is obviously entrained into the subsequent steps of the synthesis leading to 7α-methoxy-cephalosporins, with the result that these latter are contaminated by the sulphurated impurity.